2,3,3A,4,6,7,8,9,9A,9B-DECAHYDRO-4-(PHENYL OR SUBSTITUTED PHENYL)-1H-pyrrolo(3,4-h) isoquinolines

ABSTRACT

2,3,3a,4,6,7,8,9,9a,9b-Decahydro-4-(phenyl or substituted phenyl)-1H-pyrrolo(3,4-h)isoquinolines and their methods of preparation are disclosed. In addition, pharmaceutical compositions containing said compounds and methods for using said compositions as anti-inflammatory, antianginal and antiarrhythmic agents are disclosed.

United States Patent 11 1 Hauck et al.

[ Aug. 5, 1975 2,3,3A,4,6,7,8,9,9A,9B-DECAHYDRO-4- (PHENYL ORSUBSTITUTED PHENYL lH-PYRROLO( 3,4-H) ISOQUINOLINES [75] Inventors:Frederic Peter Hauck, Somerville,

N.J.; Joseph E. Sundeen, Yardley, Pa.

[73] Assignee: E. R. Squibb & Sons, Inc.,

Princeton, NJ.

22 Filed: Sept. 30, 1974 21 Appl. No.:510,205

Related U.S. Application Data [63] Continuation-impart of Ser. No.295,386, Oct. 5,

1972. abandoned. Continuation-impart of Ser. No. 295,386, Oct. 5, 1972,abandoned.

[52] U.S. Cl. 260/288 CF; 260/283 SY; 260/290 H;

260/293.72; 424/258 [51] Int. Cl. C07D 215/46; CO7D 217/12 [58] Field ofSearch 295/386; 260/288 CF [56] References Cited OTHER PUBLICATIONSGautier, Ph.D Thesis, 1966, University of New Hampshire PrimaryExaminer-Donald G. Daus Assistant ExaminerDavid E. Wheeler Attorney,Agent, or FirmLawrence S. Levinson; Merle J. Smith; Stephen B. Davis [57 ABSTRACT 3 Claims, No Drawings 1 2,3,3A,4,6,7,8,9,9A,9B-DECAHYDRO-4-(PHENYL OR SUBSTITUTED PHENYL)-lH-PYRROLO(3,4-H)ISOQUINOLINES wherein Z is phenyl or substituted phenyl; R is hydrogm,lower alkyl, or phenyl-lower alkyl; and R is hydrogen, lower alkyl,phenyl, or phenyl-lower alkyl; and pharmaceutically acceptable acidaddition salts thereof.

The term substituted phenyl is intended to encompass one or twosubstituents which may be alike or different and which are selected fromthe group consisting of lower alkyl, lower alkoxy, nitro, halogen,trifluoromethyl, cyano, carbolower alkoxy, and carboxy.

The term lower alkyl is intended to mean a straight or branched chainalkyl group of from one to eight carbon atoms.

The term lower alkoxy is intended to means a straight or branched chainalkyl group of from one to eight carbon atoms linked directly to anoxygen atom.

The compounds of the present invention may exist in a number of opticalor geometric isomeric forms such as steroisomeric forms, endo and exoforms, etc. All of these optical and geometric isomers are intended tobe within the scope of the present invention. Position isomers of thecompounds of formula IV are disclosed in copending application Ser. No.295,385 filed on Oct. 5, 1972.

The preferred compounds of this invention are those wherein R and R, aremethyl, and Z is phenyl or methoxyphenyl.

The compounds of this invention may be prepared by reacting 4-picolinewith a substituted benzaldehyde 3).. Z-E-H a to yield the intermediateof formula I. The compound of formula I is then reacted with an halideand reduced to yield the intermediate R hal reduc tion H k III offormula lll. The intermediate of formula lll is reacted with adienophile of the formula followed by reduction with lithium aluminumhydride to yield the products of formula IV.

The production of the intermediate of formula lll by this sequence isdisclosed in the Ph.D Thesis of George Gautier (University of NewHampshire, 1966).

Gautier reports the ability of an intermediate of formula ill to reactwith the dienophile N- phenylmaleimide to give the Diels-Alder Adduct.However, this same thesis reports the inability of maleic anhydride toreact with a compound of formula lll. Since maleic anhydride andN-phenylmaleimide are two of the most reactive dienophiles, the abilityof compounds of formula lll to part take in the Diels-Alder Reaction ona broad basis and not in just one isolated case seemed very much inquestion.

This invention teaches the procedures enabling one to react compounds offormula ill with most dienophiles and obtain the desired Diels-AlderAdduct.

Most dienophiles are either of an acidic nature, such as maleicanhydride, acrylic acid, fumaric acid, etc. or neutral, such asN-phenylmaleimide, ethyl acrylate, acrylonitrile, dimethyl fumarate,etc. It has been found that'dienophiles of an acidic nature in manycases will react with compounds of formula lll only wherein thecompounds of formula lll are reacted in the form of a salt of a strongacid. While this requirement is not necessary for the neutraldienophiles, it has been generally found that where strong acid salts,such as hydrochlorides, sulfates, etc. are used, cleaner reactionsresult.

Thus the reaction of maleic anhydride with the hydrochloride of lllgives the desired Diels-Alder Adduct I -HCl R1 0 III Z H c O fi 2)LL'LAlH Z 1) RNVHZ o a I, v

IVa N/ to yield the final products of formula IV.

The reaction of the salt of formula III and the dienophile are generallycarried out in a lower alkanoic acidlower alkanoic acid anhydridemixture, such as acetic acid acetic anhydride, butyric acid butyricanhydride, acetic acid propionic anhydride, etc. at a temperature rangeof from about 75 to about 175C, preferably 120 to 140C. Reaction ratesvary considerably; however, the reactions can be followed by way of thinfilm chromatography and are continued until completion which is usuallywithin a 24 hour period.

Typical dienophiles which may be employed in the process of thisinvention are given in Organic Reac- 'tions, Vol. IV, p. 23, morespecifically maleic anhydride, maleic acid, fumaric acid, diethylmaleate, diethyl fumerate, maleimide, N-substituted maleimides,acrylonitrile, ethyl acrylate, acrylic acid, etc.

The dienes are used in the form of a salt of a strong acid and the aminogroup must also be trisubstituted. Some typical examples of dienes whichmay be employed in the process of this invention are l-methyl-4- styryll,2,5 ,6-tetrahydropyridine and l-benz yl-4-pmethoxystyryl-l ,2,5,6-tetrahydropyridine.

In carrying out the initial process of this invention, a tertiary amineis employed. In order to obtainthe useful secondary amines or compoundswhichare readily prepared from secondary amines, a tertiary 1 benzylamine is employed in the Diels-Alder Reaction and removed by utilizing acatalytic amount of palladium on charcoal in an organic solvent. such asethanol in the presence of hydrogen. This reaction is of specialinterest, since one would expect the double bond to be re ducedsimultaneously; however, suchis .not the case and high yields ofdebenzylated olefin is obtained.

The resultant secondary amines are converted to other useful tertiaryamines by alkylation using alkylating agents such as dimethyl sulfate,methyl iodide, etc. or amides by acylation using acylating agents suchas acetyl chloride, propionic anhydride, etc.

The compounds of formula IV and their pharmaceutically acceptable acidaddition salts have been found to be highly useful as antiinflammatoryagents, antianginal agents and antiarrhythmic agents in mammals, such ascattle, dogs, sheep, etc. when administered in amounts ranging fromabout 0.3 mg to about 15 mg per kg of body weight per day. A preferreddosage regimen for optimum results would be from about 0.6 mg to aboutmg per kg of body weight per day, and such dosage units are employedthat a total of from about 20 mg to about 280 mg of active ingredientfor a subject of about 70 kg body weight are administered in a 24 hourperiod preferably, 40 mg to 140 The compounds of the present inventionin the described dosages are intended to be administered orally;however, other routes such as rectally, intraperitoneally,subcutaneously, intramuscularly or intravenously may beemployed. i v

The active compounds of the present inventionare orally administered,for example, with an inert diluent or with an assimilable ediblecarrier, or they may be enclosed in hard or soft gelatin capsules. orthey may be compressed into tablets, or they may be incorporateddirectly with the food of the diet. For oral therapeutic administration,the active compounds of this invention may be incorporated withexcipients and used in the form of tablets, troches, capsules, elixirs,suspensions, syrups, wafers, chewing gum, and the like. Such compositions and preparations should contain at least 0.1% of activecompound. The percentage in the compositions and preparations may, ofcourse, be varied'andmay conveniently be between about 5% to about 75%or more of the weight of the unit. The amount of active compound'in suchtherapeutically useful compositions or preparations is such that asuitable dosage willbe obtained. Preferred compositions or preparationsaccording to the present invention are prepared so that an oral dosageunit form contains between about 5 and 250 milligrams of activecompound.

The tablets, troches, pills, capsules andthe like may also contain thefollowing: a binder such as gum tragacanth, acacia, corn starch orgelatin; an excipient such I as dicalcium phosphate; a disintegratingagent such as corn starch, potato starch, alginic acid and the-like; alubricant such as magnesium stearate; anda sweetening agent such assucrose, lactose or saccharin may be added or a flavoring agent such aspeppermint, oil of Wintergreen, or cherry flavoring. When the:dosageunit form is a capsule, it may contain in addition'to materials of'theabove type a liquid carrier such as a fattyoil.

Various other materials may be present as coatings or to otherwisemodify the physical form of the dosage unit, for instance, tablets,pills, or capsules may be coated with shellac, sugar, or both. A syrupor elixir may contain the active compounds, sucrose as asweetening'agent, methyl and. propyliparabens as preservatives, a dyeand a flavoring such as cherry or orange flavor. Of course, any materialused in preparing any dosage unit form should be pharmaceutically pureand substantially non-toxic in the amounts employed.

The invention will be described in greater detail in conjunction withthe following specific examples.

EXAMPLE 1 l ,2,3,6-Tetrahydro-4-(p-methoxystyryl)- l methylpyridine,hydrochloride a. A mixture of 4-picoline (280 g, 3.0moles),:.pmethoxybenzaldehyde (410 g, 3.0 moles), and 500 ml of aceticanhydride is refluxed for 24 hours, cooled, evaporated in vacuo, and theresidue taken'upin water and basified with 10% NaOH. The solid isfiltered and crystallized from ethanol and water to give 350 g (55%) ofthe crude base. Recrystallization gives pure4-(p-methoxystyryl)-pyridine, mp l28.-130.

b. The crude 4-(p-methoxystyryl)-pyridine (160 g, 0.76 mole) in 300 mlacetonitrile is heated to effect solution, then treated with ml (2.3moles) methyl iodide, in portions. The mixture is refluxed on steam bathfor 1 hour, then cooled to afford 210 g (87%) of crys- I tallinemethiodide.

c. A solution of 100 g (0.31 mole) of the methiodide in 800 ml ofaqueous methanol is treated at 40C (cooling) with 22 g of sodiumborohydride. in portions, then stirred at 35C for 2 hours. The mixtureis cooled and extracted with ether. The dried (K CO extract isevaporated to give 60 g of crude diene amine (83%).

d. The free base (60 g) is taken up in 1 liter of isopropanol andtreated with HCl in isopropanol in excess. After 16 hours at 0C, etheris added to complete crystallization of the hydrochloride (53 g, 76%). I

e. A g sample of the crude hydrochloride is recrystallized fromisopropanol, then from isopropanolmethanol to give 6.4 g of theanalytical sample, mp 21922lC.

EXAMPLE 2 According to the method of Example 1, if one substitutes inplace of the p-methoxybenzaldehyde, an equivalent amount ofo-chlorobenzaldehyde "one obtains the hydrochloride of 1,2,3,6-tetrahydro-4-(ochlorostyryl)- l -methylpyridine.

EXAMPLES 3-5 According to the method of Example l, if one substitutes inplace of the methyl iodide, the following compounds:

ethyl iodide,

phenethyl iodide, and

i-propyl iodide, one obtains:

l,2,3,6-tetrahydro-4-(p-methoxystyryl)- l ethylpyridine hydrochloride,

l,2,3,6-tetrahydro-4-(p-methoxystyry1)-1- phenethylpyridinehydrochloride, and

1,2,3 ,6-tetrahydro-4-(p-methoxystyryl)- 1 -ipropylpyridinehydrochloride, respectively.

EXAMPLE 6 1 -Benzyl-1 ,2,3 ,6-tetrahydro-4-(p-methoxystyryl)- pyridine,hydrochloride a. A mixture of 4-pico1ine (280 g, 3.0 moles), pmethoxybenzaldehyde (410 g, 3.0 moles) and 500 ml acetic anhydride is refluxedfor 24 hours, co'oled, evaporated in vacuo, and the residue taken up inwater and basified with 10% sodium hydroxide. The solid is filtered andcrystallized from ethanol and water to give 350 g (55%) crude4-(p-methoxystyryl)-pyridine.

b. The crude styrene (84 g, 0.4 moles) in 1 liter of acetonitrile isheated to effect solution, then treated with 80 ml (0.7 moles) benzylchloride dropwise over minutes. The mixture is refluxed for 3.5 hoursunder nitrogen and allowed to cool. The crystals are filtered 109 g) anda second crop obtained by adding ether to the filtrate (9 g, 88%).

c. The crystalline benzyl chloride salt (118 g, 0.35 moles) is dissolvedin 1 liter methanol and sodium borohydride (20 g, 0.53 moles) is addedin portions with stirring (T 35C). This is stirred for 1 hour and thesolid filtered. The solid is dissolved in dichloromethane, dried(potassium carbonate), and evaporated to yield 97 g (90%) ofl-benzyl-l,2,3,6-tetrahydro-4-(pmethoxystyryl)-pyridine. I

d. The tetrahydrostyrene (64 g) is dissolved in 4 liters of ether andfiltered. Then hydrochloric acid in isopropanol is added until thesolution is acid to pH paper.

The solid is recrystallized from ethanol to yield 50.5 g

(72%) of the hydrochloride salt, mp 239-254 with decomposition.

EXAMPLE 7 1 ,2,3,6-Tetrahydro-1-methyl-4-styry1pyridine hydrochloride Toa cooled and stirred solution of 1.2.3.6-tetrahydro-1-methyl-4-styrylpyridine (53.6 g) prepared according to themethod of Gautier (Ph. D. Thesis. University of New Hampshire, 1966 p.134) in dry ether (300 ml), isopropanol saturated with dry hydrochloricacid is added until precipitation was complete. The product after etherwashing and recrystallization from methanol-ether is obtained in a 68percent yield, which melts with decomposition at 289.5-290C.

EXAMPLES 8-9 EXAMPLE 10 2,3,3a,4,6,7,8,9,9a,9b-Decahydro-4-(pmethoxyphenyl)-2,8-dimethyl-1l-l-pyrro1o[3,4-h]isoquinoline, dihydrochloride a.3a,4,6,7,8,9,9a,9b-Octahydro-4-(pmethoxyphenyl)-2,8-dimethyl-2H-pyrrolo[ 3 ,4- h]isoquinoline-l ,3-dione A solution of15 g. (0.065 moles) of 1,2,3,6- tetrahydro-4-( p-methoxystyryl 1-methylpyridine (free base of the product from example 1), 15 g. of N-methylmaleimide, 150 ml. of toluene and 20 mgs. of hydroquinone arerefluxed overnight under nitrogen. The solution is allowed to cool andevaporate. Benzene is added and evaporated twice. Water is added and theoil is extracted with benzene. The organic layers are evaporated and theresidue is crystallized, filtered, and

. washed with ether to yield 7.85 g. of 3a,4,6,7,8,9,9a,9-

b-octahydro-4-(p-methoxyphenyl)-2,8-dimethyl2H- pyrrolo[ 3,4-h]isoquinoline-1,3-dione. Recrystallization of 1.8 g. fromdichloromethane-hexane afforded 1.3 g. of an analytical sample; m.p.l29-130C.

b.2,3,3a,4,6,7,8,9,9a,9b-Decahydro-4-(pmethoxyphenyl)-2,8-dimethyl-1H-pyrro1o[3,4-hlisoquinoline, dihydrochloride A solution of 6.7 g. (0.02 moles) of3a,4,6,7,8,9,9a,9- b-octahydro-4-(p-methoxyphenyl)-2,8-dimethyl-2H-pyrrolo[3,4-h]isoquinoline-1,3-dione from part (a) in 100 ml. ofdichloromethane-ether (1:1) is added to a slurry of 3 g. (0.08 moles) oflithium aluminum hydride in 300 ml. dichoromethane-ether (1:1) undernitrogen. This is refluxed for 18 hours. Saturated sodium carbonatesolution is added at room temperature until the reaction is white. Thesalts are filtered and washed with dichloromethane. The combinedfiltrates are evaporated to yield 5.5 g.2,3,3a,4,6,7,8,9,9a,9bdecahydro-4-(p-methoxyphenyl)-2,8-dimethyl-1H-pyrrolol3,4-h]isoquinoline. This is dissolved in isopropanol-ether, andhydrochloric acid in isopropanol is 7 added until the solution is acidicto pH paper. Excess ether is added and the white solid filtered.Recrystallization of this solid from isopropanol-methanol-ether affordsan analytical sample of about 3.1 g., mp. 273C.

EXAMPLE 1 1 2,3,3a,4,6,7,8,9,9a,9b-DecahydroA-phenyl-Z,8-

dimethyl l H-pyrrolo[ 3.4-h ]isoquinoline, dihydrochloride a.l,2,3,4,6,7,'8,8a-Octahydro-2-methyl-6-phenyl- 7,8-isoquinolinedicarboxylic acid anydride, hydrochloride A solution of 50 g. maleicanhydride and I g. 1,2,3,- 6-tetrahydro-l-methyl-4-styrylpyridinehydrochloride, from example 7, in 100 ml. acetic acid and 100 ml. aceticanhydride previously thoroughly sparged with dry nitrogen is refluxedgently for 3 hours under nitrogen. The reaction mixture is concentratedto 100 ml. volume, and flushed with 300 ml. benzene to remove most ofthe remaining solvent. The residue is triturated with benzene severaltimes to give 17.5 g. of a crude brown product. This compound is notfurther purified. it is refrigerated in the dry state for storage.

b. 2,3,,3a,4,6,7,8,9,9a,9b-Decahydro-4-phenyl-2,8-dimethyl-lH-pyrrolo[3,4-h1isoquinoline, dihydrochloride 1 The anhydridefrom part (a) is added portionwise to a stirred solution of aqueousmethylamine. The solution is heated to boil off the water. The heatingis continued with stirring until the evolution of gas ceases and thereaction mixture is maintained at from 200 to 225C for about one-half to1 hour. The resulting product is reduced with lithium aluminum hydrideaccording to the procedure of example l0(b) to yield and titled product.

Alternatively, the titled product can be prepared by following theprocedure of example but employingl,2,3,6-tetrahydro-l-methyl-4-styrylpyridine in part (a) of example 10.

EXAMPLE 12 Following the procedure of example 10 but employing 1,2,3,6-tetrahydro-1-benzyl-4-styrylpyridine in part (a) of example 10,one obtains the titled product.

Similarly, by employing the compounds of an'y'of examples 2 to 6, 8, or9 in the procedure of example l0 other compounds within the scope of theinvention are The active ingredient, starch and magnesium stearate areblended together. The mixture is usedto fill hard shell capsules of asuitable size at a'fill weight of'300 milligrams per capsule.

What is claimed is:

1. A compound of the formula: I,

wherein Z is selected from the group consisting of phenyl andmethoxyphenyl; and R and R are methyl; and the pharmaceuticallyacceptable acid addition salts thereof. I

2. The compound of claim 1 wherein Z is pmethoxyphenyl.

3. The compound of claim I wherein Z is phenyl.

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTIQNPATENT NO. ,236

DATED 3 Aug. 5, 1975 lNV.ENTOR(5) i F. P. Hauck et al It is certifiedthat error appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

Col. 1, line 33, "means" should read -mean-.

Col 5, line 61 (T 35C) should read (T 5 Col. 6, line 48, "dimethylZH"should read dimethyl2H-.

Col. 6, line 60, "dichoromethane" should read dichloro methane.

Col. 7, line 45, "methyllH" should read methyl-lH-.

Signed and Scaled this seventh Day of Omaha r1975 [SEAL] Arrest:

RUTH C. MASON C. MARSHALL DANN Arresting Officer Commissioner uj'larenrsand Trademarks

1. A COMPOUND OF THE FORMULA:
 2. The compound of claim 1 wherein Z isp-methoxyphenyl.
 3. The compound of claim 1 wherein Z is phenyl.